All of the cytokine antagonists which are currently available have been developed for systemic administration. This is because all were developed to treat systemic illnesses, including rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, or Crohn's Disease.
The use of cytokine antagonists to treat neurological disorders is discussed in several previous patents of this inventor, including U.S. Pat. Nos. 6,015,557, 6,177,077, 6,419,944 B2, 6,537,549 and U.S. patent application 20030049256 of this inventor. These issued patents and patent applications are incorporated in their entirety herein.
The adverse biologic effects of excess TNF can be reduced by the use of biologic inhibitors of TNF. These inhibitors can be divided into two broad categories: monoclonal antibodies and their derivatives; and TNF binding biologics which are not antibody based. In the first category belong infliximab (Remicade®, Centocor), adalimumab (Humira®, Abbott), and CDP 870 (Celltech). All of these monoclonal antibody based anti-TNF biologics are clearly distinct from the TNF binding proteins of this invention, both functionally and biologically. For example, both adalimumab and infliximab have the ability to lyze cells directly, a property which is not shared by etanercept, and a property which is not advantageous for the present invention. In fact the ability to lyze cells is deleterious for CNS applications. The second category includes etanercept, pegylated soluble TNF receptor type 1 (Amgen) and onercept (Serono). The uses of etanercept, pegylated soluble TNF receptor type 1 and onercept for the purposes of this patent are therefore distinguished from those of both adalimumab and infliximab, and other monoclonal antibody-derived anti-TNF products in development, such as CDP 870.
The biologic TNF inhibitors which are the subject of this patent are the non-monoclonal antibody TNF biologics. The three products of this type which have advanced the furthest in development are etanercept, a fusion protein which contains two p75 soluble TNF receptors fused to an Fc fragment of an IgG1 immunoglobulin; and two distinct p55 receptor derivatives: pegylated soluble TNF receptor type 1 and onercept, also referred to as TNF-binding protein-1. Etanercept has a serum half life of approximately 4.8 days when administered to patients with rheumatoid arthritis on a chronic basis; onercept has a serum half-life which is considerably shorter, and it is usually administered at least three times weekly when used to treat systemic illnesses.
Perispinal administration of a TNF binding biologic when compared to systemic administration, carries with it one or more of the following advantages for the present invention:                1) greatly improved efficacy due to improved delivery of the therapeutic molecule to the brain via both the vertebral venous system (VVS) and the CSF.        2) greater efficacy due to the achievement of higher local concentration in the interspinous space, leading to improved delivery to the VVS and the CSF.        3) greater efficacy due to the ability of the administered therapeutic molecule to reach the brain without degradation caused by hepatic or systemic circulation;        4) more rapid onset of action;        5) longer duration of action; and        6) Potentially fewer side effects, due to lower required dosage.        
Clinical experience utilizing perispinal administration of etanercept for treating lumbar and cervical radiculopathy and other forms of neuropathic pain caused by vertebral disc disease has demonstrated the dramatic efficacy, and the extraordinarily rapid onset of action produced by perispinal administration of etanercept for these disorders (see Tobinick references 14, 15, and 16). Etanercept, in part due to its molecular weight, has difficulty in crossing the blood-brain barrier when administered systemically. In this invention perispinal administration of etanercept provides a route of administration which allows etanercept to bypass the blood-brain barrier and/or blood-nerve barrier in therapeutic amounts for treating the neurological conditions of consideration herein when it is administered in therapeutic doses of 25 mg to 100 mg to the interspinous space, or in even lower dosage if delivered directly to the epidural space.
Specific inhibitors of TNF, only recently commercially available, now provide the possibility of therapeutic intervention in TNF mediated disorders. These agents have been developed to treat systemic illnesses, and therefore have been developed for systemic administration. Various biopharmaceutical companies have developed TNF antagonists to treat systemic illnesses: Immunex Corporation developed etanercept (Enbrel®) to treat rheumatoid arthritis and Serono is developing onercept, a recombinant TNF binding protein (r-TBP-1) for treating rheumatoid arthritis and psoriasis/psoriatic arthritis.
Etanercept can also be designated as TNFR:Fc because it is a dimeric fusion protein consisting of two soluble TNF receptors fused to a Fc portion of an immunoglobulin molecule. This fusion protein functions in a manner quite distinct from a simple soluble TNF receptor. Soluble TNF receptors are normally present in the human body. But the use of these soluble TNF receptors as therapeutic agents for the treatment of the conditions of consideration in this patent is made impractical by their extremely short half-life and therefore their limited biologic activity. The present invention utilizing etanercept is therefore distinguished from an invention specifying the use of a soluble TNF receptor. It is incorrect and imprecise to describe etanercept as a soluble TNF receptor because this is an incorrect description of its complex structure and omits characteristics of etanercept which are absolutely essential to its biological functions, including the avidity of its binding to TNF. This is further underscored by the developmental history of etanercept. In its first iteration the precursor molecule to etanercept was produced with a single TNF receptor fused to an immunoglobulin fragment. The biologic activity of this molecule was poor. Therefore not only is etanercept distinguished from a soluble TNF receptor, it is also distinguished from a TNF-binding fusion protein which contains the recombinant DNA sequence of only a single soluble TNF receptor. The unique structure of etanercept, containing a dimer (two) soluble TNF receptors fused to an Fc portion of an immunoglobulin molecule, is necessary for the proper performance of the present invention. Since etanercept has the molecular structure of a fusion protein it is thus quite distinct from both onercept and pegylated soluble TNF receptor type 1.